Alexis Díaz-García, Ángel Garrido, Jenny Laura Ruiz-Fuentes, Tamara Hermosilla, Diego Varela
{"title":"蝎毒诱导人非小肺癌细胞系G2/M细胞周期阻滞和凋亡细胞死亡。","authors":"Alexis Díaz-García, Ángel Garrido, Jenny Laura Ruiz-Fuentes, Tamara Hermosilla, Diego Varela","doi":"10.1590/1678-9199-JVATITD-2024-0035","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Non-small cell lung cancers (NSCLC) represent the primary cause of cancer-related deaths worldwide. <i>Rhopalurus junceus</i> venom has been shown to exert cytotoxic effects against a panel of epithelial cancer cells <i>in vitro</i> and suggested that NSCLC was the subtype most susceptible to the treatment.</p><p><strong>Methods: </strong>This study evaluated the effect of <i>Rhopalurus junceus</i> scorpion venom on cell viability, in non-cancerous (MRC-5, lung; CHO-K1, ovary) and NSCLC (A549; NCI-H460) cell lines. The effects on cell cycle, apoptosis, and cell signaling-related proteins were determined by flow cytometry and WB. Protein fractions responsible for the observed effect were identified using HPLC.</p><p><strong>Results: </strong>Scorpion venom was more effective against NSCLC than non-cancerous cells. E<sub>max</sub> values were 20.0 ± 5.8% and 22.47 ± 6.02% in A549 and NCI-H460 cancer cells, respectively, as compared to 50 ± 8.1% in MRC-5 and 54.99 ± 7.39% in CHO-K1 cells. It arrested NSCLC cells in the G2/M phase, while non-cancerous cells were arrested in the S (MRC-5) or G0/G1 (CHO-K1) phases. No changes were observed in the Bax/Bcl-2 or the cleaved-caspase 3/Total caspase 3 ratios in cells treated with venom. Likewise, the scorpion venom treatment did not affect p-ERK, p-AKT, or p-38MAPK protein levels. In contrast, scorpion venom treatment increased the cytosolic apoptosis-inducing factor (AIF) in A549 cells, indicating caspase-independent apoptosis. Additionally, combined etoposide/venom exposure provoked G2/M arrest and apoptosis in NSCLC more strongly than either substance alone. Furthermore, upon crude venom fractioning through RP-HPLC, we found two soluble fractions with high cytotoxic effects.</p><p><strong>Conclusion: </strong>The present study concludes that a specific fraction of <i>Rhopalurus junceus</i> venom reduces cell viability of NSCLC cells. The AIF protein plays a key role in mediating caspase-independent apoptotic cell death. These findings suggest that <i>Rhopalurus junceus</i> venom enhances the anticancer effect of etoposide <i>in vitro</i> by causing cell cycle arrest and caspase-independent apoptosis.</p>","PeriodicalId":17565,"journal":{"name":"Journal of Venomous Animals and Toxins Including Tropical Diseases","volume":"31 ","pages":"e20240035"},"PeriodicalIF":1.8000,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792888/pdf/","citationCount":"0","resultStr":"{\"title\":\"<i>Rhopalurus junceus</i> scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines.\",\"authors\":\"Alexis Díaz-García, Ángel Garrido, Jenny Laura Ruiz-Fuentes, Tamara Hermosilla, Diego Varela\",\"doi\":\"10.1590/1678-9199-JVATITD-2024-0035\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Non-small cell lung cancers (NSCLC) represent the primary cause of cancer-related deaths worldwide. <i>Rhopalurus junceus</i> venom has been shown to exert cytotoxic effects against a panel of epithelial cancer cells <i>in vitro</i> and suggested that NSCLC was the subtype most susceptible to the treatment.</p><p><strong>Methods: </strong>This study evaluated the effect of <i>Rhopalurus junceus</i> scorpion venom on cell viability, in non-cancerous (MRC-5, lung; CHO-K1, ovary) and NSCLC (A549; NCI-H460) cell lines. The effects on cell cycle, apoptosis, and cell signaling-related proteins were determined by flow cytometry and WB. Protein fractions responsible for the observed effect were identified using HPLC.</p><p><strong>Results: </strong>Scorpion venom was more effective against NSCLC than non-cancerous cells. E<sub>max</sub> values were 20.0 ± 5.8% and 22.47 ± 6.02% in A549 and NCI-H460 cancer cells, respectively, as compared to 50 ± 8.1% in MRC-5 and 54.99 ± 7.39% in CHO-K1 cells. It arrested NSCLC cells in the G2/M phase, while non-cancerous cells were arrested in the S (MRC-5) or G0/G1 (CHO-K1) phases. No changes were observed in the Bax/Bcl-2 or the cleaved-caspase 3/Total caspase 3 ratios in cells treated with venom. Likewise, the scorpion venom treatment did not affect p-ERK, p-AKT, or p-38MAPK protein levels. In contrast, scorpion venom treatment increased the cytosolic apoptosis-inducing factor (AIF) in A549 cells, indicating caspase-independent apoptosis. Additionally, combined etoposide/venom exposure provoked G2/M arrest and apoptosis in NSCLC more strongly than either substance alone. Furthermore, upon crude venom fractioning through RP-HPLC, we found two soluble fractions with high cytotoxic effects.</p><p><strong>Conclusion: </strong>The present study concludes that a specific fraction of <i>Rhopalurus junceus</i> venom reduces cell viability of NSCLC cells. The AIF protein plays a key role in mediating caspase-independent apoptotic cell death. These findings suggest that <i>Rhopalurus junceus</i> venom enhances the anticancer effect of etoposide <i>in vitro</i> by causing cell cycle arrest and caspase-independent apoptosis.</p>\",\"PeriodicalId\":17565,\"journal\":{\"name\":\"Journal of Venomous Animals and Toxins Including Tropical Diseases\",\"volume\":\"31 \",\"pages\":\"e20240035\"},\"PeriodicalIF\":1.8000,\"publicationDate\":\"2025-02-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11792888/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Venomous Animals and Toxins Including Tropical Diseases\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1590/1678-9199-JVATITD-2024-0035\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q4\",\"JCRName\":\"TOXICOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Venomous Animals and Toxins Including Tropical Diseases","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1590/1678-9199-JVATITD-2024-0035","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q4","JCRName":"TOXICOLOGY","Score":null,"Total":0}
Rhopalurus junceus scorpion venom induces G2/M cell cycle arrest and apoptotic cell death in human non-small lung cancer cell lines.
Background: Non-small cell lung cancers (NSCLC) represent the primary cause of cancer-related deaths worldwide. Rhopalurus junceus venom has been shown to exert cytotoxic effects against a panel of epithelial cancer cells in vitro and suggested that NSCLC was the subtype most susceptible to the treatment.
Methods: This study evaluated the effect of Rhopalurus junceus scorpion venom on cell viability, in non-cancerous (MRC-5, lung; CHO-K1, ovary) and NSCLC (A549; NCI-H460) cell lines. The effects on cell cycle, apoptosis, and cell signaling-related proteins were determined by flow cytometry and WB. Protein fractions responsible for the observed effect were identified using HPLC.
Results: Scorpion venom was more effective against NSCLC than non-cancerous cells. Emax values were 20.0 ± 5.8% and 22.47 ± 6.02% in A549 and NCI-H460 cancer cells, respectively, as compared to 50 ± 8.1% in MRC-5 and 54.99 ± 7.39% in CHO-K1 cells. It arrested NSCLC cells in the G2/M phase, while non-cancerous cells were arrested in the S (MRC-5) or G0/G1 (CHO-K1) phases. No changes were observed in the Bax/Bcl-2 or the cleaved-caspase 3/Total caspase 3 ratios in cells treated with venom. Likewise, the scorpion venom treatment did not affect p-ERK, p-AKT, or p-38MAPK protein levels. In contrast, scorpion venom treatment increased the cytosolic apoptosis-inducing factor (AIF) in A549 cells, indicating caspase-independent apoptosis. Additionally, combined etoposide/venom exposure provoked G2/M arrest and apoptosis in NSCLC more strongly than either substance alone. Furthermore, upon crude venom fractioning through RP-HPLC, we found two soluble fractions with high cytotoxic effects.
Conclusion: The present study concludes that a specific fraction of Rhopalurus junceus venom reduces cell viability of NSCLC cells. The AIF protein plays a key role in mediating caspase-independent apoptotic cell death. These findings suggest that Rhopalurus junceus venom enhances the anticancer effect of etoposide in vitro by causing cell cycle arrest and caspase-independent apoptosis.
期刊介绍：
Journal of Venomous Animals and Toxins including Tropical Diseases (JVATiTD) is a non-commercial academic open access publication dedicated to research on all aspects of toxinology, venomous animals and tropical diseases. Its interdisciplinary content includes original scientific articles covering research on toxins derived from animals, plants and microorganisms. Topics of interest include, but are not limited to:systematics and morphology of venomous animals;physiology, biochemistry, pharmacology and immunology of toxins;epidemiology, clinical aspects and treatment of envenoming by different animals, plants and microorganisms;development and evaluation of antivenoms and toxin-derivative products;epidemiology, clinical aspects and treatment of tropical diseases (caused by virus, bacteria, algae, fungi and parasites) including the neglected tropical diseases (NTDs) defined by the World Health Organization.
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